Bone destruction in inflammatory erosive arthritis, such as rheumatoid arthritis (RA), is associated with increased production of pro-inflammatory cytokines, which promote focal bone resorption by increasing the differentiation of osteoclast precursors (OCP) to mature osteoclasts in inflamed joints. Recent progress in Osteoimmunology indicates that osteoclasts are not only bone resorbing cells; they also produce factors that contribute to inflammation and autoimmunity by autocrine and paracrine mechanisms. However, osteoclast-produced factors that could affect the development and progression of RA directly have not been well studied. Using microarray analysis, we identified that VEGF-C expression is significantly increased in OCPs from TNF- Tg arthritic mice. VEGF-C is a lymphogenic growth factor essential for lymphoangiogenesis. But its role in osteoclast function has not been investigated and little is known about the role of the lymphatic system in the pathogenesis of joint destruction in RA. To explore the involvement of VEGF-C in this setting, we carried out a series preliminary studies and demonstrated that 1) RANKL and TNF induce VEGF-C expression in OCPs and OCs; 2) VEGF-C stimulates osteoclastic bone resorption; 3) RA joints have remarkably increased lymphatic vessel formation; and 4) inhibition of VEGF-C signaling reduces the severity of joint inflammation in TNF-Tg mice. Based on these findings, we hypothesize that in inflammatory joints OCPs and OCs are activated by RANKL and TNF to produce VEGF-C, which mediates joint inflammation and bone erosion simultaneously by stimulating vasculogenesis and osteoclastogenesis via autocrine and paracrine mechanisms. These hypotheses will be tested in 3 specific aims. In Aim 1, we will investigate the mechanisms by which RANKL and TNF stimulate OCPs and osteoclasts to produce VEGF-C. In Aim 2, we will examine the effects of VEGF-C on osteoclast function and the downstream signaling pathways involved. In Aim 3, we will determine the functional importance of VEGF-C signaling in the pathogenesis of RA using a VEGFR3 blockade approach. These studies will provide new information on how OCPs stimulate pannus formation via lymphangiogenesis. Ultimately they should lead to the development of novel specific therapeutic agents to prevent and treat patients with inflammatory erosive arthritis. PUBLIC HEALTH RELEVANCE. The proposed study is aimed to investigate the role of bone resorbing osteoclasts in the development and progression of rheumatoid arthritis by affecting osteoclast function and lymphangiogenesis in mouse models of arthritis. The results will enhance our understanding of osteoclast and lymphatic biology and provide new direction for developing a novel therapy to treat arthritis.